tbuckley/cabot-search huggingface dataset:
Pathological response and tumor immune microenvironment remodeling of neoadjuvant ALK-TKIs in NSCLC with ALK.
Authors: Li Li, Nan Zheng, Yi Min Zhang, Ruiguang Zhang, Yong He, Fang Wu
Journal: Journal of Clinical Oncology (2023)

e20574 Background: Anaplastic lymphoma kinase–tyrosine kinase inhibitor (ALK-TKI; ALKi) has shown potent antitumor activity in metastatic non–small-cell lung cancer (NSCLC) with ALK rearrangement (ALK+). However, its efficacy in neoadjuvant settings for patients with ALK+ resectable NSCLC has been poorly explored. Given this, the present study aimed to examine the clinical activity and tumor immune microenvironment (TIME) remodeling of neoadjuvant ALKi therapy. Methods: In this retrospective study, ALK+ NSCLC patients treated with neoadjuvant ALKi therapy at three hospitals in China were enrolled between February 2018 and April 2022.Data on clinical features, radiographic responses, and pathological responses were collected and evaluated. Multiplex immunofluorescence was performed on pre-treatment biopsy specimens and surgically resected specimens to investigate the impact of ALKi on TIME. Two panels (Panel 1: CD8, PD1, GB, CK, 4′,6-diamidino-2-phenylindole [DAPI]; Panel 2: CD4, FOXP3, CD68, CD163, CK, DAPI) were used to identify multiple immune cell types. Results: A total of 12 patients with stage IIA to IIIB NSCLC who received neoadjuvant ALKi therapy and R0 resection were enrolled; the median age was 54.0 years, and 66.7% (8/12) were female. The median duration of neoadjuvant ALKi was 5.5 months. The objective response rate was 91.7% (11/12). All patients successfully underwent R0 resection. The major pathological response (MPR) rate was 75.0% (9/12), with 58.3% (7/12) achieving a pathological complete response (pCR). After neoadjuvant ALKi therapy, we observed asignificant increase in immune infiltration of total CD8+ (histochemistry score: median, 10.51 vs 24.01, P= 0.028; density: median, 128.38 vs 694.09 cells/mm2, P= 0.028; percentage: median, 3.53% vs 15.92%, P= 0.028) and total CD4+ (density: median, 275.56 vs 651.82 cells/mm2, P= 0.028; percentage: median, 5.98% vs 10.46%, P= 0.028). Similar results were found for CD4+FOXP3+, CD8+PD1+, CD8+PD1-, CD8+GB+, and CD8+GB-. However,macrophages, including CD68+CD163- M1 and CD68+CD163+ M2 macrophages, showed little change after neoadjuvant ALKi therapy. When comparing TIME between neoadjuvant ALKi and PD1 inhibitors in resected specimens from patients with pCR, neoadjuvant ALKi therapy presented higher levels of CD8+PD1+ but lower levels of CD8+GB+. Conclusions: Neoadjuvant ALKi therapy achieved an encouraging MPR rate of 75% and enhanced immune infiltration, suggesting its safety and feasibility for ALK+ resectable NSCLC. This study advances our understanding of TIME remodeling by neoadjuvant ALKi therapy and merits further investigation in the neoadjuvant setting for patients with ALK+ resectable NSCLC.
Impact of the COVID pandemic on reporting of breast cancer cases and mortality.
Authors: Rhami Khorfan, Jukes P. Namm, Halley P Vora, Naveenraj Livingstone Solomon, Sharon S. Lum
Journal: Journal of Clinical Oncology (2023)

e18842 Background: The National Cancer Database (NCDB) introduced COVID-specific variables in 2020 to assess the impact of the pandemic on cancer care. Variables include (1) any SARS-CoV-2 test and (2) SARS-CoV-2 test result. We evaluated patterns of breast cancer reporting and mortality compared to pre-pandemic. Methods: From the 2020 NCDB breast cancer participant user file, we separately examined reporting and mortality in the years 2017-2020. Pre-pandemic years (2017-2019) were used as a baseline to evaluate secular trends not related to the pandemic. For patients diagnosed in the study period, patient/hospital factors associated with complete reporting (CR) or no reporting (NR) of COVID variables were compared. For patients who died during the study period, yearly mortality rate and overall survival (OS) were examined overall and by stage. Patient/hospital factors were examined for associations with year of death. Results: Fewer breast cancer cases were reported in 2020 (232,023) compared to 2019 (268,210) and 2018 (260,259). In 2020, there were 97,810 (42%) with NR and 116,455 (50%) with CR of COVID variables. On multivariable analysis, patients with NR were more likely to be &gt; 70 years old, of Asian race, with Medicare coverage, lower education quartile, and treated at community hospitals and those in the Middle Atlantic region. There were 60,933 deaths in 2020, 64,502 in 2019, 63,865 in 2018, and 61,930 in 2017. There were significantly fewer stage 4 deaths in 2020 compared to prior (Table). Although there was a steady trend of increasing OS across the 4-year period, the incremental increase from 2019 to 2020 was higher than expected based on previous years. This finding was particularly true for stage 4 patients (median OS: 31.4 months in 2020, 20.2 months in 2019). On multivariable analysis, 2020 mortalities were less likely in patients &gt; 80 years old (OR 0.88, p &lt; .01) or with stage 3 (0.81, p &lt; .01) or stage 4 (0.64, p &lt; .01) disease, and more likely at academic centers (1.05, p &lt; .01) than in 2017-2019. Conclusions: Non-reporting of COVID data is not at random, and is more common in populations at risk. In addition, fewer breast cancer mortalities were reported in 2020, with higher than expected OS. These findings suggest that OS was artificially increased in 2020 due to underreporting of patients who may be at higher risk of mortality. Accurate and complete data is crucial for evaluating the pandemic's impact on patient care. Underreporting of patients who may be most vulnerable limits our ability to comment on the true impact of the pandemic. These limitations must be considered to avoid blind spots in evaluation of pandemic data and risk deepening disparities. [Table: see text]
Spectrum of acquired <i>KRAS </i>mutations in driver mutation-positive non-small cell lung cancer.
Authors: Joshua E. Reuss, Nishant Gandhi, Phillip Walker, Jorge J. Nieva, Jean Gabriel Bustamante Alvarez, Jennifer W Carlisle, Aakash Desai, Ari M. Vanderwalde, Patrick C. Ma, Stephen V. Liu
Journal: Journal of Clinical Oncology (2023)

9069 Background: With the emergence of effective targeted-therapies for KRAS G12C, and the development of promising agents for KRAS G12V and G12D among others, the identity of unique KRAS mutations in non-small cell lung cancer (NSCLC) has become increasingly relevant. Acquired KRAS mutations are a known mechanism of resistance observed across driver mutation-positive (DM+) NSCLC. The incidence and diversity of these acquired alterations, and whether they differ from those observed in de novo KRAS-mutated NSCLC, is unknown. Methods: NSCLC molecular profiles were obtained using next-generation sequencing (Caris Life Sciences) with paired whole-transcriptomic sequencing (Illumina NovaSeq) and immunohistochemistry (Caris Life Sciences). Demographic data were abstracted from medical records. KRAS mutation diversity was defined for de novo KRAS-mutated ( KRASmt) NSCLC ( KRAS as only identified driver – KRASmt_dn) and DM+ NSCLC with acquired KRAS mutations (concurrent KRASmt with other known driver – KRASmt_acq). Fisher’s exact test was used to compare the distribution of unique KRAS mutations between the groups. Due to the unique biology of NSCLC with class II/III BRAF mutations, this subset was removed from the KRASmt_acq subgroup for the final analysis. Results: A total of 5932 KRASmt NSCLC samples were identified, among which 5879 were KRASmt_dn and 53 were KRASmt_acq (see table). The distribution of unique KRAS mutations was not significantly different between groups (p = 0.14). Within the KRASmt_dn group, KRAS G12C was most common (40%), followed by G12V (19%), G12D (14%), G12A (7%) and Q61H/G13C (4% each). In the KRASmt_acq group, KRAS G12C was most common (30%), followed by G12D (19%), G12V (17%), Q61H (11%), G12A (7%), and G13C (6%). The most common observed driver mutations in the KRASmt_acq group were EGFR (38%) and MET (30%). In the EGFR group, KRAS G12D (25%), Q61H/G12C (20% each), G12V/G13C (10% each), and G12F/A/R (5% each) were observed. In the MET group, KRAS G12C (25%), G12D/V/A (19% each), Q61H (12%) and G12S (6%) were seen. Among 7 patients with a documented history of smoking in the KRASmt_acq group, KRAS G12D and Q61H were most common (29% each), followed by G12V/F and G13C (14% each). Conclusions: While the distribution of unique KRAS mutations did not differ significantly between KRASmt_dn and KRASmt_acq groups, acquired KRAS mutations were seen across DM+ NSCLC subsets, among which the frequency of observed mutations appeared to vary. The functional and immunological significance of these mutations, and their impact on clinical outcomes, warrants further investigation. [Table: see text]
Real world data evidence (RWDE) on cancer patients' (pts) awareness and knowledge of cancer associated thrombosis (CAT) events.
Authors: Adrian Marcelo Duek, Bozhena Haikin, Alon Litvin, Daniel A. Vorobiof
Journal: Journal of Clinical Oncology (2023)

e18774 Background: Cancer pts are mostly unaware of the higher than normal risk of developing a CAT event. A recently reported European survey, with 745 participants, showed that just above two-thirds (69%) of pts never received information and were not aware of the higher thrombotic risk associated with cancer diagnosis and its diverse treatments. Methods: A comprehensive survey was sent, during July-September 2022, to members of Belong.life, a social and professional international free application for cancer pts and their caregivers. Pts who registered within the diagnostic groups, received a 24 questions survey of demographic and specialized questions referring to their knowledge on the possible increased risk of associated thromboembolic events, as well as determine the available resources for pts education. 1200 adult pts with a variety of cancers, replied to the survey. Most pts were receiving active anticancer treatments. Independent demographic and clinical variables were analyzed. Results: 1200 cancer pts, Belong users from English speaking countries, completed the survey, most of them females (74%, 889/1200) and &gt; 50 years of age (85%,1014/1200). Commonest cancers were breast (29%,350/1200), gastrointestinal (15%,182/1200), lung (12%,144/1200) and gynecological (11%,142/1200). 80% (964/1200) never suffered thrombosis before their cancer diagnosis. Overall, at the time of answering the survey, 71% (861/1200) claimed not being aware of their CAT risks. 28% (339/1200) of the responders were aware of CAT at the time of replying to the survey, and of them only 17% (49/289) confirmed to be fully informed of CAT risks. Among all those that received information on CAT, 10% (120/1200) obtained it at the time of their first thrombotic event occurrence, while 14% (172/1200) were informed at the time of their cancer diagnosis and/or commencement of their planned treatments. Verbal information on CAT was mostly conveyed (51%) by the medical staff, in face to face meetings, while family and friends gave mostly internet and social media guidance (73%). Conclusions: The presence of a CAT impacts cancer pts clinical outcomes and quality of life. Available data on CAT education and awareness have been sparse. A recent European survey has shown important awareness gaps. Our RWDE survey, on 1200 Belong members with diverse geographical backgrounds and a variety of cancers, confirmed that 71% of the surveyed pts are not aware of their CAT risks before their diagnosis and/or treatment of cancer, indicating a major need for education on the known CAT risk factors, signs and symptoms, and available diagnostic imaging and treatment approaches. It is imperative that oncologists, together with allied medical professionals involved in cancer care, provide relevant CAT information, at the time of a patient’s cancer diagnosis, when individual treatments are planned, and along the pts’s cancer journey.
Analysis of ATM germline mutations in solid tumors from Chinese patients.
Authors: Tao Fu, Yaping Zhao, Didi Guo, Siqi Chen, Tiantian Han, Ran Ding, Wanglong Deng, Fanfeng Bu
Journal: Journal of Clinical Oncology (2023)

10586 Background: Ataxia-telangiectasia mutated (ATM) is a tumor suppressor genes and plays an important role in the repair of DNA double-strand breaks (DSBs). Germ-line mutations of ATM gene result in the well-characterized ataxia telangiectasia syndrome, which manifests with an increased cancer predisposition, including a 20% to 30% lifetime risk of lymphoid, gastric, breast, central nervous system, skin, and other cancers. Novel therapies are in development that may improve the response to therapy of patients with ATM-deficient cancers including targeted therapy and immunotherapy. Nevertheless, the knowledge of incidence of ATM germline mutations in solid tumor remains poorly understood. Methods: We identified 19248 malignant solid tumors patients without selecting age or family history in a retrospective cohort. The pathogenicity of germline mutations was categorized based on American College of Medical Genetics and Genomics (ACMG) guidelines.The patients were divided into two groups, P/ LP group (with pathogenic or likely-pathogenic mutations), and Non-P/LP group (neither pathogenic nor likely-pathogenic mutation). Results: In 19248 patients with pan-cancer, 76 patients were found 76 heterozygous pathogenic or likely pathogenic germline mutations in ATM gene and the mutation frequency was 0.39%.Among these 76 carriers, 71 (93.4%) carried frameshift, nonsense or splice mutations (33 for frameshift,21 for missense and 17 for splice mutations). 4 carried missense mutations and 1 carried intron mutations. Eliminated a few types of cancers that had a smaller number (less than 50), the higher frequency of mutations contained cancers were pancreatic cancer (1.0%,7/692), breast cancer (0.71%,3/423), gastric cancer (0.6%,7/1094), The median age of group P/LP and non-P/LP group was 64 and 63 in pancreatic cancer，62 and 53 in breast cancer and 62 and 61 in gastric cancer. The three genes with the most somatic mutations were TP53, MUC16 and KRAS in P/LP group and were TP53, MUC16 and EGFR in non-P/LP group. There was no significant difference in mutation frequency of the four genes. The media TMB in P/LP group and non-P/LP group were 3.55 and 2.84 respectively and there was no statistical difference. In P/LP group，only one patients is high microsatellite instability who carryied a MLH1 and a ATM pathogenic mutation. Conclusions: This was the first report of the incidence of ATM germline mutations in Chinese solid tumors which expanded the understanding of ATM and provided a direction for clinical trial design of novel therapies. The relationship between germline mutations and cancer susceptibility will be studied in the future.
Correlation between step count and clinical outcomes for patients with cancer during treatment: A feasibility study.
Authors: Ingrid Oakley-Girvan, Reem Yunis, Kate Lyden, Sharon W Davis, Yaya Zhai, Jen Blakenship, Ai Kubo, Raymond Liu, Elad Neeman
Journal: Journal of Clinical Oncology (2023)

e18804 Background: Step count, as measured by a wearable accelerometer, has been shown to have a relationship to premature death, cardiovascular events, functional decline, longer stay, and higher rehospitalization rates. However, few cancer studies or trials have incorporated accelerometers to measure response to active treatment. We developed the DigiBioMarC™ smartphone application for cancer patients to enable participation in decentralized clinical trials and remote cancer care by collecting informed consent, ePROs and accelerometer data using an Apple Watch. This analysis assessed whether daily step data were associated with participants clinical events. Methods: We tested the feasibility of the DigiBioMarC application along with the Apple Watch for approximately 4 weeks with 50 cancer patients undergoing IV chemotherapy or immunotherapy recruited in a fully decentralized study through Kaiser Permanente Northern California. Participants used the app for at least 28 days and were provided with an Apple Watch if they did not already have one. Data pre-processing was performed to identify periods of missing data and non-wear time. Step count was calculated for each calendar day and days that included at least ten hours of wear time while awake were considered sufficient and included in the analysis. Specific clinical events were collected from the patients’ electronic health records (EHR) up to six months following the study. Results: Thirteen participants experienced at least one clinical event, and there were 5 deaths. Using Cox regression, patients with more sufficient days were less likely to die during follow up (p = 0.122) than patients with fewer sufficient days. On sufficient days, median daily steps &lt; = 2,510 were associated with one or more adverse clinical events, while daily steps &gt; 2,510 were associated with no clinical events and had a longer time to adverse clinical event (p = 0.068) compared to those with less than or equal to 2,510 median daily steps on sufficient days. Daily median step count on sufficient days predicted clinical event occurrence with an accuracy of 0.833. Conclusions: Findings from this feasibility study support the hypothesis that daily stepping behavior is a valid real-world digital measure to predict clinical events in patients undergoing cancer treatment. Although the predictive models did not reach statistical significance (p &lt; 0.05), this is likely due to the low frequency of clinical events in the dataset. These findings indicate that future investigations with larger sample sizes are warranted as this may be a beneficial tool for decentralized trials or care when patients have longer periods of time between clinical visits. In patients undergoing cancer treatment, real-world based step data extracted from wearables can provide early indication of poor or declining health.
A comparative analysis of next-generation sequencing based on plasma cfDNA and tumor tissue DNA in patients with advanced lung cancer.
Authors: Tian Li, Jingmin Lin, Suo Peisu, Yingmei Li, Shifu Chen, Yunfan Wang
Journal: Journal of Clinical Oncology (2023)

e21021 Background: Although liquid biopsy based on plasma cell-free DNA (cfDNA) provides a non-invasive detection method for cancer patients, tissue biopsy is still the gold standard for molecular subtyping. The concordance of these two techniques has been evaluated in certain cohorts. The comparison of plasma cfDNA and tissue DNA NGS ina large Chinese cancer cohort is yet to be analyzed. Methods: We retrospectively reviewed HaploX's genomic sequencing data from July 2021 to December 2022 to assess the concordance between plasma cfDNA and cancer tissue DNA. A total of 589 advanced lung cancer patients with matched tissue and plasma sample were included in the study. Tissue and peripheral blood was collected at the same time during surgical operation or biopsy. Tissue DNA and plasma cfDNA were isolated and prepared for the NGS with commercially available kits. The positive percent agreement (PPA) between plasma cfDNA sequencing and tissue sequencing, the negative percent agreement (NPA), positive predictive value (PPV), negative predictive value (NPV), and overall percent agreement (OPA) were calculated and compared. Results: The positive percent agreement (PPA) of plasma cfDNA sequencing compared with tissue sequencing were 78% (EGFR, 82%; KRAS, 71%; HER2 mutation, 76%; BRAF V600E mutation, 75%; ALK fusion, 74%; RET fusion, 60%; ROS1 fusion,33.3%; MET exon14 skipping, 50%). EGFR mutations included EGFR p.L858R,19del, p.C797S, p.L861Q, p.T790M, KRAS mutations included p.G12X and p.Q61X.， HER2 mutations included gain-of-function mutations；NPA was 92.4%，PPV was 93.8%，NPV was 74.4%，OPA was 84%. Conclusions: The positive mutation detection consistency of plasma cfDNA sequencing and tissue sequencing in advanced lung cancer patients is 78%, indicating that liquid biopsy based on plasma cfDNA is reliable in most advanced lung cancer patients, but there are some limitations in gene fusion and MET exon 14 jumping detection. Liquid biopsy based on plasma cfDNA can meet most clinical genomic testing needs in general, especially when tissue is not available, but physicians need to be more cautious with negative results. Keywords: Liquid biopsy, Next-generation sequencing (NGS), Concordance Analysis, Lung Cancer.
Treatment patterns of triple-class refractory (TCR) multiple myeloma (MM) across the United States (US), Canada, and western Europe: A real-world observational chart review study.
Authors: Ravi K. Goyal, Gaelle Frugier, Julien Rombi, Lizzi Esterberg, Keith L. Davis, Patrick Hlavacek, Jinma Ren, Alex Schepart, Didem Aydin, Marco DiBonaventura
Journal: Journal of Clinical Oncology (2023)

e18827 Background: Most patients with MM eventually become refractory to the three main therapy classes used to treat the disease: proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mAbs). The objective of the present study was to describe the management of patients who have become TCR and how treatment strategies vary across countries. Methods: A retrospective chart review study was conducted across the US, Canada (CA), the UK, France (FR), Germany (DE), Spain (ES), Belgium (BE), the Netherlands (NL), and Sweden (SE). Oncologists/hematologists were recruited to abstract medical chart information from eligible patients (eg, diagnosed with MM, clinician-reported refractoriness to ≥1 IMiD, ≥1 PI, and ≥1 anti-CD38 antibody treatment) into an electronic case report form. Patients had to initiate their first (index) therapy after becoming TCR between 11/1/2015 and 12/31/2019. Chart abstractions were performed from February through October 2022. Demographics, baseline clinical characteristics, and treatment patterns were descriptively analyzed. Results: A total of 718 patients with TCR MM were included (61.4% male; median age at index = 64.2 years); 25.8% had an ECOG score of 2 and 28.7% had high cytogenetic risk [ie, t(4:14), t(14:16), and/or del(17p)]. Patients received a median of 3 treatment lines prior to their index therapy (19.4% were penta-exposed). In the post TCR setting, the most frequently used treatments included IMiDs (52.5%), PIs (40.8%), chemotherapy (CT; 27.3%), and mAbs (16.3%). Treatment class usage also varied significantly by country (Table 1). Conclusions: Our global chart review indicated that many patients reach TCR status after only a few lines of therapy and, after this point, retreating with IMiDs, PIs, and mAbs was common practice. The diversity of treatment classes used in this setting underscores the challenges across countries with managing a TCR population due to the lack of a clear standard of care. [Table: see text]